Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome
Authors: Robert F. J. Kullberg, Justin de Brabander, Leonoor S. Boers, Jason J. Biemond, Esther J. Nossent, Leo M. A. Heunks, Alexander P. J. Vlaar, Peter I. Bonta, Tom van der Poll, JanWillem Duitman, Lieuwe D. J. Bos, W. Joost Wiersinga, Anno Saris, Heder De Vries, Lilian J. Meijboom, Siebe G. Blok, Alex R. Schuurman, Tom D.Y. Reijnders, Juan J. Garcia Vallejo, Hetty Bontkes, René Lutter, Harm Jan Bogaard, S. de Bruin, R. Koning, M.A. van Agtmael, A.G. Algera, F.E.H.P. van Baarle, D.J.C. Bax, M. Beudel, M. Bomers, M. Botta, G.J. de Bree, M. Bugiani, E.B. Bulle, O. Chouchane, A.P.M. Cloherty, P.E. Elbers, L.M. Fleuren, S.E. Geerlings, B.F. Geerts, T.B.H. Geijtenbeek, A.R.J. Girbes, A. Goorhuis, M.P. Grobusch, F.M.J. Hafkamp, L.A. Hagens, J. Hamann, V.C. Harris, R. Hemke, S.M. Hermans, M.W. Hollmann, J. Horn, J.W. Hovius, M.D. de Jong, N. van Mourik, J.F Nellen, F. Paulus, E. Peters, B. Preckel, S.J. Raasveld, M. Schinkel, M.J. Schultz, K. Sigaloff, M.R. Smit, C. Stijnis, W. Stilma, C.E. Teunissen, P. Thoral, A.M. Tsonas, M. van der Valk, D.P. Veelo, M. van Vugt, D. Wouters, A.H. Zwinderman, M.C. Brouwer, D. van de Beek
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19–related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42–0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42–0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19–related ARDS.